Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations

Rosell, Rafael; Molina, Miguel Ángel; Costa, Carlota; Simonetti, Sara; Giménez-Capitán, A.; Bertrán-Alamillo, Jordi; Mayo, Clara; Morán, Teresa; Méndez, Pedro Rafael Casado; Cardenal, Felipe; Isla, Dolores; Provencio, Mariano; Cobo, Manuel; Insa, Amelia; García‐Campelo, Rosario; Reguart, Noemı́; Majem, Margarita; Viteri, Santiago; Carcereny, Enric; Porta, R.; Massutí, Bartomeu; Queralt, Cristina; Aguirre, Itziar de; Sánchez, José Miguel; Sanchez-Ronco, María; Mate, José Luís; Ariza, Aurelio; Benlloch, Susana; Sánchez, José Javier; Bivona, Trever G.; Sawyers, Charles L.; Tarón, Miquel

doi:10.1158/1078-0432.ccr-10-2158

Cited by 274 publications

(253 citation statements)

References 45 publications

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“…an area greater than 2.2 mm 2 were macrodissected; the rest of the samples were microdissected as previously described (21). In both cases, cells were dissected directly into 30 mL of PCR buffer (Ecogen) plus proteinase K (40 mg/mL) and incubated overnight at 60 C. Proteinase was inactivated by incubation at 100 C for 10 minutes and the resulting cell extract used for mutational analyses.…”

Section: Translational Relevancementioning

confidence: 99%

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

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138

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Purpose: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function.Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P ¼ 0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P ¼ 0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P ¼ 0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.

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Section: Translational Relevancementioning

confidence: 99%

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Molina-Vila

Bertrán-Alamillo

Gasco

et al. 2014

Clinical Cancer Research

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138

149

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“…Rosell et al revealed that 80 of 129 patients with advanced NSCLC harboring EGFR mutations had responded to erlotinib (ORR is 68.9) in their cohort study [16]. In EURTAC, which was performed in a first-line setting, ORR was reported as 64% [5].…”

Section: Motoshima Et Al Page 13mentioning

confidence: 99%

Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics

Motoshima

Nakamura

Sano

et al. 2013

Cancer Chemother Pharmacol

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“…Unfortunately, around 60% of these patients develop resistance to anti-EGFR treatment through a missense point mutation resulting in an amino-acid change from threonine to methionine in exon 20 of EGFR (EGFR T790M) (7)(8)(9)(10)(11)(12). This mutation is thought to not only appear during treatment, but in rare cases (<5%) can also be found in primary tumors not previously treated with TKIs (5,7,(13)(14)(15)(16). Detecting the T790M mutation is therefore of critical importance in guiding the treatment of NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

Exosome-Based Detection of EGFR T790M in Plasma from Non–Small Cell Lung Cancer Patients

Castellanos-Rizaldos

Grimm

Tadigotla

et al. 2018

Clinical Cancer Research

181

129

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Tumor tissue biopsies carry risks and are not always possible, making liquid biopsies an attractive way to acquire molecular information from cancer patients. The EGFR T790M mutation is a critical biomarker in non-small cell lung cancer and has introduced new challenges in how these patients are managed. With the approval of osimertinib for patients failing first generation EGFR inhibitor therapy, the use of a liquid biopsy to detect EGFR T790M would reduce the number of unnecessary repeat biopsies. Detection of EGFR T790M using cfDNA has proved to be challenging due to low abundance in blood. Here we present a novel EGFR T790M assay based on a platform validated in a CLIA laboratory that simultaneously monitors the mutation on exosomal RNA/DNA and cfDNA from plasma that achieves 92% sensitivity and 89% specificity.Research. AbstractPurpose: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a non-invasive option to detect the mutation, however sensitivity is low as many patients have too few detectable copies in circulation. Here we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele specific qPCR.Experimental design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples.The T790M mutation status was determined using an analytically validated allelespecific qPCR assay in a CLIA laboratory.Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging.Research.on March 26,

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Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations

Cited by 274 publications

References 45 publications

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics

Exosome-Based Detection of EGFR T790M in Plasma from Non–Small Cell Lung Cancer Patients

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